Tibolone (C21H28O2; (7α,17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one) is a synthetic steroid with oestrogenic, progestonic and weak androgenic properties. It is used for the treatment of oestrogen deficiency symptoms in postmenopausal women, more than one year after menopause and for prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.
A typical known formulation of tibolone is a 100 mg tablet comprising 2.5 mg of tibolone, a relatively small amount (e.g. about 1% by weight) of pharmaceutically acceptable auxiliaries such as an antioxidant and/or a lubricant, and a carrier making up the body of the tablet. The carrier is typically composed of about 10% by weight of starch, e.g. potato starch, and about 90% by weight of lactose.
Tibolone, when formulated as a solid dosage form, in particular a tablet, is however relatively unstable. The inherent stability is at least partly due to the presence of degradation products, in particular 10,17-dihydroxy-7α-methyl-19-nor-10ξ,17α-pregn-4-en-20-yn-3-one (impurity A), 10-hydroxyperoxy-17-hydroxy-7α-methyl-19-nor-10ξ,17α-pregn-4-en-20-yn-3-one (impurity B), and 17-hydroxy-7α-methyl-19-nor-10ξ,17α-pregn-4-en-20-yn-3-one (impurity C), which increase during production of the tablets and during storage. Impurity C is the most difficult to control.
Various attempts have been reported to improve tibolone stability in tablets. EP 0389035 describes a manufacturing process for tibolone tablets which ensures the stability of tibolone. The obtained tablets are available on the market under the name of Livial®. The process encompasses placebo granulation followed by mixing with tibolone, but is complicated and quite expensive. WO 98/47517 pretends to obtain better stability when using a high (more than 10% by weight) percentage of a starch in the tibolone formulation. WO 03/032924 teaches that the inclusion of a pH-adjusting agent increases the stability of tibolone formulations. WO 2005/117899 describes the use of water-soluble starch products, in particular cyclodextrin, as carriers for enhancing storage stability of tibolone formulations. WO 2004/045587 addresses the problem of the tibolone instability by providing the tibolone tablets with a coating. WO 2009/012733 is directed to a manufacturing process for tibolone tablets by direct compression, characterized in that the formulation is exposed to the action of a protic solvent during the process, resulting in more stable tablets.
WO2017047586A1 for example discloses a drug formulation comprising a combination of starch as a desintegrant and mannitol as a diluent.
The present invention aims to provide a tibolone formulation with improved stability, which can be obtained by a simple manufacturing process.